This invention relates to novel compositions of matter comprising a lipophilic oligosaccharide antibiotic, and to pharmaceutical formulations containing such compositions of matter and to methods of making and using such pharmaceutical compositions to treat and/or prevent microbial infections in animals especially mammals such as human beings.
Lipophilic oligosaccharide antibiotics including, for example, everninomicins, curamycins, avilamycins and flambamycins are members of the orthosomycin family of antibiotics which contain at least one acidic phenolic hydrogen, and two orthester linkages associated with carbohydrate residues. See for example. A. K. Ganguly in "Kirk-Othmer, Encyclopedia of Chemical Technology", (1978), Volume 2, pp. 205-209, Third Edition, John Wiley and Sons and W. D. Oillis, et al., Tetrahedron (1979), Volume 35, pp. 105-127. These lipophilic oligosaccharide antibiotics exhibit broad spectrum biological activity against gram positive and some gram negative bacteria in various in vitro-assays, and in-vivo activity in animal models such as mice, but to date no pharmaceutically acceptable formulation of such antibiotics useful for vivo administration has been available. Thus, we have observed that injection of these lipophilic oligosaccharide antibiotics cause an adverse reaction syndrome. The term "adverse reaction syndrome" as used herein means symptoms of the following type observed in animals such as mice upon parenteral administration of lipophilic oligosaccharide antibiotics: incoordination, ataxia, lateral recumbency, urination, hind leg rigidity, labored breathing, and arrest. Thus, in summary, there are no known pharmaceutically acceptable compositions of these lipophilic oligosaccharide antibiotics for the safe and effective use of these potent antibiotics in animals including mammals such as human beings.
Cyclodextrins are modified starches made from glucopyranose units and include .alpha.-cyclodextrin consisting of six glucopyranose units, .beta.-cyclodextrin consisting of seven glucopyranose units, and .gamma.-cyclodextrin consisting of eight glucopyranose units. The .alpha.-, .beta.- and .gamma.-cyclodextrins and derivatives thereof have an inside surface or cavity which is lipophilic and an outer surface which is hydrophilic. This combination of a hydrophobic cavity and a hydrophilic outer surface has led to the use of cyclodextrins and derivatives thereof for the molecular complexation or encapsulation of many hydrophobic and/or unstable drugs of suitable dimensions, thereby improving solubility, stability and bioavailability of such drugs. Derivatives of .alpha.-, .beta.- and .gamma.-cyclodextrins for example hydroxypropyl-.beta.-cyclodextdrins are disclosed by Jozsef Szejtli in Pharmaceutical Technology, Jun. 1991, 36-40.
Complexes of .alpha.-, .beta.- and .gamma.-cyclodextrins, mixtures and derivatives thereof are disclosed in, for example, N. Bodor U.S. Pat. No. 4,983,586. The Bodor U.S. Pat. No. 4,983,586 discloses a method of decreasing the incidence of precipitation of a lipophilic or water labile drug occurring at/or near the injection site and/or in the lungs following parenteral administration, by parenterally administering said drug in an aqueous solution containing a large quantity, i.e., 20 to about 50 weight percent of hydroxypropyl-.beta.-cyclodextrin.
Josef Pitha in U.S. Pat. No. 4,727,064 and The International J. of Pharmaceutics, (1986) 29, 73-82 disclose the use of a concentrated, i.e., 40-60 weight percent, aqueous solution of hydroxypropyl-.beta.-cyclodextrin to solubilize various drugs such as acetaminophen, sex steroids, cardiac glycosides such as digoxin, as well as retinoic acid and acid salts thereof. See also the Pitha U.S. Pat. No. 4,596,795 which discloses the administration of the sex hormones, testosterone, progesterone and estradiol as complexes with poly-.beta.-cyclodextrin or hydroxypropyl-.beta.-cyclodextrin.
The Bodor and Pitha references make no reference to phenols or lipophilic oligosaccharide antibiotics.
Janssen Pharmaceutica N. V. International Pat.ent Application No. PCT/EP84/00417 published under International Publication No. WO 85/02767 on 4, Jul. 1985 discloses pharmaceutical compositions comprising complexes of drugs which are unstable or only sparingly soluble in water with partially etherified .beta.-cyclodextrin (".beta.-CD") of the Formula (.beta.-CD)-OR wherein the residue R is hydroxyethyl, hydroxypropyl, dihydroxypropyl and part of the residue R may optionally be alkyl groups, especially methyl or ethyl.
If the drug molecule has basic or add groups which may possibly be used to increase water solubility by salt formation, the Janssen International Publication No. WO 85/02767 teaches that salt formation as a rule results in decreased efficacy or impaired chemical stability and thus, salt formation to solubilize poorly water soluble acidic and basic compounds is discouraged. There is no disclosure of lipophilic oligosaccharide antibiotics or the compositions of the present invention.
Various strains of bacteria such as gram-positive cocci, e.g., streptococci and enterococci as well as methicillin-resistant and methicillinsusceptible staphylococci have become resistant to commercially available antibiotics, e.g., vancomycin.
Thus, there is a need for pharmaceutically acceptable compositions for treating bacterial infections including methicillin-resistant and methicillin-susceptible stapliylococci and vancomycin-resistant bacteria. There is also a need for pharmaceutically acceptable compositions containing a lipophilic oligosaccharide antibiotic active against a broad range of susceptible gram-positive and gram-negative bacterial infections, especially pharmaceutical compositions adapted for parenteral use which avoid occurrence of the adverse reaction syndrome.